NIH Consensus Development Conference on Management of Hepatitis C
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Interferon Alfa-n 1 Trials
Geoffrey C. Farrell, M.D., F.R.A.C.P.
Background
Lymphoblastoid interferon (IFN-alpha-n1) is produced from a human lymphoid cell line and consists of multiple IFN-alpha subtypes of which at least two are glycosylated. (1) This differs from the recombinant IFNs, which are single unglycosylated proteins produced from individual IFN-alpha genes (usually subtype 2) expressed in E. coli. The differences between IFN-alpha preparations provide a potential basis for varying clinical effects. A meta- analysis of earlier published trials indicated that IFN-alpha-n1 was at least as efficacious against hepatitis C as recombinant products (IFN-alpha2b, IFN-alpha2a). (2) One apparent difference, however, was a lower rate of posttreatment relapse after IFN-alpha-n1 . Thus, sustained response (SR) was 25 percent with IFN-alpha-n1 compared with 16 percent for recombinant products. In order to provide sufficient power to detect a 10 percent difference in response rate between lymphoblastoid and recombinant IFN-alpha, a randomized, clinical trial (the 096 study) was conducted at 63 centers in 13 countries.
Methods
Patients had previously untreated, chronic hepatitis C virus (HCV) infection, defined by positive anti- HCV, consistently raised alanine aminotransferases (ALT), appropriate liver histology, and exclusion of other disease. Patients (n=1071) were randomized to receive lymphoblastoid interferon (IFN-alpha-n1) or recombinant interferon-alfa2b (IFN-alpha2b), both 3 million units (MU) tiw subcutaneously for 24 weeks. HCV genotype (by line probe assay) and serum HCV RNA titer (by quantitative polymerase chain reaction [PCR]) were determined at baseline.
Primary endpoints were: end-treatment response (ETR}two or more successively normal serum ALT levels including the week 24 value; sustained response (SR)~continued normal ALT after an ETR, with normal values at weeks 48 (week 48 SR) and 72 (week 72 SR). Secondary endpoints were serum HCV RNA at weeks 24, 48, and 72 , and quantitative histology (by Knodell’s histologic activity index [HAI] score) at weeks 24 and 72. Primary endpoints were analyzed by intent to treat, and secondary endpoints were according to treatment received.
Results
Groups were well matched for demographic, viral, clinical, and histologic variables; about 10 percent had cirrhosis. Predominant genotypes were la and lb in the United States, and types lb, 2a, and 3a in Europe and Australia. At end of treatment, ALT response was 35.3 percent for IFN-alpha-n1 and 37.9 percent for IFN-alpha2b (NS). The type and frequency of reported adverse experiences were similar; 26 patients (5 percent) receiving IFN-alpha-n1 and 19 (4 percent) receiving IFN-alpha2b withdrew because of adverse experiences. Viral and histologic responses were determined in the 970 evaluable patients. At 24 weeks, there was no difference between the groups in the proportion who were HCV RNA negative (IFN-alpha-n1, 37.9 percent vs. IFN-alpha2b, 42.0 percent, NS). More than 70 percent of ALT responders had cleared serum HCV RNA. Among patients who had an ETR, liver histology at 24 weeks was improved (2-point or greater reduction in HAI activity score) in 61 percent; there were no differences between treatment groups. Among responders (ETR), posttreatment relapse was less frequent with IFN-alpha-n1 than with IFN-alpha2b. Thus sustained ALT responses (SR) to IFN-alpha-n1 were more frequent than to IFN-alpha2b (12.0 percent vs 7.6 percent at 48 weeks, P=O.OI; 10.3 percent vs 6.7 percent at 72 weeks, P=0.02).
Relapse was more likely if HCV RNA was present at end treatment. SR was associated with viral loss, and more patients treated with IFN-alpha-n1 were HCV RNA negative at week 72 compared with IFN-alpha2b (9.9 percent vs. 5.7 percent, p Sixteen candidate variables were examined by multivariate regression analysis in relation to treatment response. Heavier weight, cirrhosis at screen, and genotypes 1 were associated with lack of ETR, whereas larger body surface area and white race were positively associated with ETR. Viral titer was not associated with ETR, but was independently associated with SR.
SR varied from 3 percent with genotype 1, to 20 percent for genotypes 2, 3, and mixed infections. SR (72 weeks) after treatment with IFN-alpha-n1 was superior across all genotypes compared with IFN-alpha2b.
Discussion
The finding that IFN-alpha-n1 conferred an efficacy advantage compared with a recombinant alphainterferon when given at 3 MU, tiw for 24 weeks was not due to a greater number of patients having an ETR. Rather, it was attributable to the lower proportion of patients who subsequently relapsed. This reduction in relapse rate produced a higher SR for IFN-alpha-n1, and more patients treated with IFN-alpha-n1 had sustained clearance of serum HCV RNA. The findings of this prospective study are consistent with the earlier meta-analysis of interferon trials for hepatitis C; i.e., there is no difference between lymphoblastoid and recombinant alpha-interferon products in ETR, but 50 percent improvement in SR with the lymphoblastoid interferon due to a lower relapse rate. (2) It appears likely that the clinical difference in efficacy results from IFN-alpha-n1 exerting more potent anti-HCV activity across all HCV genotypes. The greater diversity of alpha-interferon subtypes present in the Iymphoblastoid product might be responsible for this.
The present results provide more extensive data concerning the posttreatment course following 24 weeks of treatment with IFN-alpha than have been previously available. The proportion of patients with normalization of ALT who were negative with regard to HCV RNA in serum increased from 70 percent at end treatment, to 80 percent at 48 weeks and 90 percent at 72 weeks. This indicates a relationship between sustained ALT normalization and clearance of HCV RNA. The minority of ALT responders who remain HCV RNA positive are likely to undergo clinical relapse in the year following treatment. The present data also confirm that sustained ALT and viral response are associated with histologic improvement of liver inflammation and necrosis, but not of fibrosis.
Several studies with recombinant IFN-alpha have shown that treatment courses of 12 months (or longer) reduce the relapse rate by around 50 percent, thereby effectively doubling SR. (3) Data regarding the comparative efficacy of higher interferon doses have been conflicting, and improvement in efficacy may be compromised by a higher rate of intolerable adverse experiences. (3-4) The issue therefore arises as to whether lymphoblastoid interferons also exhibit greater potency when administered in higher doses or for longer. This was addressed in a large European multicenter trial (091 ) of IFN-alphan l. (5) Entry and response criteria were similar to the 096 study; SR was at 48 week followup. Patients (n=440) were randomly assigned to receive one of the following four regimens (all tiw): 3 MU for 24 weeks, 3 MU for 48 weeks, 5 MU for 24 weeks, and 5 MU for 48 weeks. ETR ranged from 38 percent to 50 percent (NS). There was no difference in SR between the 24 weeks 3 MU and 5 MU arms [6 percent vs. 14 percent, NS] or between the corresponding two 48- week arms (19 percent vs. 20 percent, NS). However, at both dose increments, prolongation of therapy to 12 months effectively doubled the SR (P=O.OO 1 ) by halving the relapse rate. Histological improvement, as seen by reduction in the necroinflammatory activity of the HAI score, was most effectively maintained in the group receiving 5 MU for 48 weeks
Conclusions
IFN-alpha-n1 and IFN-alpha2b have similar ETR rates and safety profiles, but the SR rate is higher with IFN-alpha-n1. Sustained response was associated with loss of HCV viremia and with histologic improvement, the latter being maximal in those who exhibited clearance of HCV RNA. HCV genotype was the most powerful determinant of SR, and the greater efficacy of Iymphoblastoid interferon appeared to extend to all major genotypes. There is definite evidence that 12 months of treatment is superior to 6 months in terms of ALT and HCV RNA as efficacy endpoints, and whether there is truly benefit for histologic response at the higher dose of IFN-alpha-n1 (5 MU vs. 3 MU tiw) needs to be considered in relation to adverse experiences. Finally, the possibility that Iymphoblastoid interferons could produce a better SR than recombinant alpha-interferons when given for a 12-month (or longer) treatment course is an important issue that requires further study.
References
1.Zoon K, et al. Purification and characterization of multiple components of human lymphoblastoid interferon-alpha. J Biol Chem 1992;1267:15210-6.
2.Bardelli F, Messori A, Rampazzo R, Alberti A, Martini N. Effect of recombinant or lymphoblastoid interferon-alpha on alanine aminotransferase in patients with chronic hepatitis C or chronic non-A non-B hepatitis. A meta-analysis. Clin Drug Invest 1995;9:239-54.
3.Poynard T, Leroy V, Cohard M, Thevenot T, Mathurin P, Opolon P, Zarski JP. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1 996;24:778-9.
4.Lindsay KL, Davis GL, Schiff ER, et al. Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatology 1996;24:1034-40.
5.Marcellin P, Hopf U, Trepo C, et al. A randomized, double-blind, controlled, multicenter study of lymphoblastoid interferon alpha-nI in the treatment of adults with chronic hepatitis C. J Hepatol. In press.
